Health inequalities in rural China: evidence from HeBei Province

The purpose of this study was to examine the degree to which commonly used social class indicators-education, income, and occupation-are associated with health in the context of rural China. Data were collected from 10,226 individuals of working age (16-60) living in HeBei Province, the PRC. The association between education and income observed resembles the patterns documented in industrial societies, but the health status of farmers is quite similar to that of white collar employees. Persons in other than mainstream occupations report the poorest health status. Social selection and the costs of relative deprivation appear to be useful to the understanding of health inequality in rural China, though in a manner shaped by the particular social context.     

Circulating endothelial progenitor cells are up-regulated in a mouse model of endometriosis

Endometriosis is a debilitating disease characterized by the growth of ectopic endometrial tissue. It is widely accepted that angiogenesis plays an integral part in the establishment and growth of endometriotic lesions. Recent data from a variety of angiogenesis-dependent diseases suggest a critical role of bone marrow-derived endothelial progenitor cells (EPCs) in neovascularization. In this study we examined the blood levels of EPCs and mature circulating endothelial cells in a mouse model of surgically induced endometriosis. Fluorescence-activated cell sorting analysis revealed elevated levels of EPCs in the blood of mice with endometriosis compared with control subject that underwent a sham operation. EPC concentrations positively correlated with the amount of endometriotic tissue and peaked 1 to 4 days after induction of disease. In a green fluorescent protein bone marrow transplant experiment we found green fluorescent protein-positive endothelial cells incorporated into endometriotic lesions but not eutopic endometrium, as revealed by flow cytometry and immunohistochemistry. Finally, treatment of endometriosis-bearing mice with the angiogenesis inhibitor Lodamin, an oral nontoxic formulation of TNP-470, significantly decreased EPC levels while suppressing lesion growth. Taken together, our data indicate an important role for bone marrow-derived endothelial cells in the pathogenesis of endometriosis and support the potential clinical use of anti-angiogenic therapy as a novel treatment modality for this disease.     

Epoxyeicosanoids stimulate multiorgan metastasis and tumor dormancy escape in mice

Epoxyeicosatrienoic acids (EETs) are small molecules produced by cytochrome P450 epoxygenases. They are lipid mediators that act as autocrine or paracrine factors to regulate inflammation and vascular tone. As a result, drugs that raise EET levels are in clinical trials for the treatment of hypertension and many other diseases. However, despite their pleiotropic effects on cells, little is known about the role of these epoxyeicosanoids in cancer. Here, using genetic and pharmacological manipulation of endogenous EET levels, we demonstrate that EETs are critical for primary tumor growth and metastasis in a variety of mouse models of cancer. Remarkably, we found that EETs stimulated extensive multiorgan metastasis and escape from tumor dormancy in several tumor models. This systemic metastasis was not caused by excessive primary tumor growth but depended on endothelium-derived EETs at the site of metastasis. Administration of synthetic EETs recapitulated these results, while EET antagonists suppressed tumor growth and metastasis, demonstrating in vivo that pharmacological modulation of EETs can affect cancer growth. Furthermore, inhibitors of soluble epoxide hydrolase (sEH), the enzyme that metabolizes EETs, elevated endogenous EET levels and promoted primary tumor growth and metastasis. Thus, our data indicate a central role for EETs in tumorigenesis, offering a mechanistic link between lipid signaling and cancer and emphasizing the critical importance of considering possible effects of EET-modulating drugs on cancer.     

Agonist-specific voltage sensitivity at the dopamine D2S receptor--molecular determinants and relevance to therapeutic ligands

Voltage sensitivity has been demonstrated for some GPCRs. At the dopamine D(2S) receptor, this voltage sensitivity is agonist-specific; some agonists, including dopamine, exhibit decreased potency at depolarized potentials, whereas others are not significantly affected. In the present study, we examined some of the receptor-agonist interactions contributing to these differences, and investigated how dopamine D(2S) receptor voltage sensitivity affects clinically used dopamine agonists. GIRK channel activation in voltage-clamped Xenopus oocytes was used as readout of receptor activation. Structurally distinct agonists and complementary site-directed mutagenesis of the receptor's binding site were used to investigate the role of agonist-receptor interactions. We also confirmed that the depolarization-induced decrease of dopamine potency in GIRK activation is correlated by decreased binding of radiolabeled dopamine, and by decreased potency in G protein activation. In the mutagenesis experiments, a conserved serine residue as well as the conserved aspartate in the receptor's binding site were found to be important for voltage sensitive potency of dopamine. Furthermore, the voltage sensitivity of the receptor had distinct effects on different therapeutic D(2) agonists. Depolarization decreased the potency of several compounds, whereas for others, efficacy was reduced. For some agonists, both potency and efficacy were diminished, whereas for others still, neither parameter was significantly altered. The present work identifies some of the ligand-receptor interactions which determine agonist-specific effects of voltage at the dopamine D(2S) receptor. The observed differences between therapeutic agonists might be clinically relevant, and make them potential tools for investigating the roles of dopamine D(2) receptor voltage sensitivity in native tissue.     

NKG2D ligands mediate immunosurveillance of senescent cells

Cellular senescence is a stress response mechanism that limits tumorigenesis and tissue damage. Induction of cellular senescence commonly coincides with an immunogenic phenotype that promotes self-elimination by components of the immune system, thereby facilitating tumor suppression and limiting excess fibrosis during wound repair. The mechanisms by which senescent cells regulate their immune surveillance are not completely understood. Here we show that ligands of an activating Natural Killer (NK) cell receptor (NKG2D), MICA and ULBP2 are consistently up-regulated following induction of replicative senescence, oncogene-induced senescence and DNA damage - induced senescence. MICA and ULBP2 proteins are necessary for efficient NK-mediated cytotoxicity towards senescent fibroblasts. The mechanisms regulating the initial expression of NKG2D ligands in senescent cells are dependent on a DNA damage response, whilst continuous expression of these ligands is regulated by the ERK signaling pathway. In liver fibrosis, the accumulation of senescent activated stellate cells is increased in mice lacking NKG2D receptor leading to increased fibrosis. Overall, our results provide new insights into the mechanisms regulating the expression of immune ligands in senescent cells and reveal the importance of NKG2D receptor-ligand interaction in protecting against liver fibrosis.